CA2750716A1

CA2750716A1 - Derive de pyrimido-pyrimido-indazole

Derive de pyrimido-pyrimido-indazole Download PDF

Info

Publication number: CA2750716A1
Authority: CA; Canada
Prior art keywords: group; pyrimido; indazol; alkyl group; amino
Prior art date: 2009-02-25
Legal status : Abandoned

Application number

CA2750716A

Other languages

English (en)

Inventor

Yasuhiro Goto

Kenji Niiyama

Satoshi Sunami

Keiji Takahashi

Current Assignee

MSD KK

Original Assignee

MSD KK

Priority date

2009-02-25

Filing date

2010-02-18

Publication date

2010-09-02

2010-02-18 Application filed by MSD KK filed Critical MSD KK

2010-09-02 Publication of CA2750716A1 publication Critical patent/CA2750716A1/fr

Status Abandoned legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 claims abstract description 502
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 174
125000005843 halogen group Chemical group 0.000 claims abstract description 145
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 132
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 52
125000003118 aryl group Chemical group 0.000 claims abstract description 48
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 47
239000002246 antineoplastic agent Substances 0.000 claims abstract description 28
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 28
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 24
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 11
238000004519 manufacturing process Methods 0.000 claims description 639
-1 perhydro-1,4-diazepinyl group Chemical group 0.000 claims description 328
125000000217 alkyl group Chemical group 0.000 claims description 178
125000001424 substituent group Chemical group 0.000 claims description 133
230000001093 anti-cancer Effects 0.000 claims description 60
150000003839 salts Chemical class 0.000 claims description 49
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
125000000623 heterocyclic group Chemical group 0.000 claims description 36
238000002360 preparation method Methods 0.000 claims description 35
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 34
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 29
229910052757 nitrogen Inorganic materials 0.000 claims description 28
150000001204 N-oxides Chemical class 0.000 claims description 27
125000000753 cycloalkyl group Chemical group 0.000 claims description 27
102000014150 Interferons Human genes 0.000 claims description 26
108010050904 Interferons Proteins 0.000 claims description 26
VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 23
150000002148 esters Chemical class 0.000 claims description 23
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 22
229940079322 interferon Drugs 0.000 claims description 22
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 17
125000004430 oxygen atom Chemical group O* 0.000 claims description 17
KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 16
229940127093 camptothecin Drugs 0.000 claims description 16
125000004093 cyano group Chemical group *C#N 0.000 claims description 16
229910052697 platinum Inorganic materials 0.000 claims description 15
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 15
125000001931 aliphatic group Chemical group 0.000 claims description 14
229940127084 other anti-cancer agent Drugs 0.000 claims description 14
125000004043 oxo group Chemical group O=* 0.000 claims description 14
229910052717 sulfur Inorganic materials 0.000 claims description 14
125000004434 sulfur atom Chemical group 0.000 claims description 14
125000003342 alkenyl group Chemical group 0.000 claims description 13
125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 13
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 12
SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
229940100198 alkylating agent Drugs 0.000 claims description 11
239000002168 alkylating agent Substances 0.000 claims description 11
230000000340 anti-metabolite Effects 0.000 claims description 11
229940100197 antimetabolite Drugs 0.000 claims description 11
239000002256 antimetabolite Substances 0.000 claims description 11
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125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 11
229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 11
239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 11
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 10
125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 10
125000001041 indolyl group Chemical group 0.000 claims description 10
125000003226 pyrazolyl group Chemical group 0.000 claims description 10
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GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 8
239000003085 diluting agent Substances 0.000 claims description 8
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239000008194 pharmaceutical composition Substances 0.000 claims description 8
RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 7
239000003242 anti bacterial agent Substances 0.000 claims description 7
VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 7
239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 6
ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 6
229940088710 antibiotic agent Drugs 0.000 claims description 6
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239000003937 drug carrier Substances 0.000 claims description 6
VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 6
125000002541 furyl group Chemical group 0.000 claims description 6
XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 6
239000000367 immunologic factor Substances 0.000 claims description 6
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125000004193 piperazinyl group Chemical group 0.000 claims description 6
125000004076 pyridyl group Chemical group 0.000 claims description 6
125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
229960001674 tegafur Drugs 0.000 claims description 6
WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 claims description 6
125000000335 thiazolyl group Chemical group 0.000 claims description 6
UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 6
BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 5
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BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 5
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DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 5
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DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 5
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125000003386 piperidinyl group Chemical group 0.000 claims description 5
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RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 5
125000001544 thienyl group Chemical group 0.000 claims description 5
229960000303 topotecan Drugs 0.000 claims description 5
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STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
WLCZTRVUXYALDD-IBGZPJMESA-N 7-[[(2s)-2,6-bis(2-methoxyethoxycarbonylamino)hexanoyl]amino]heptoxy-methylphosphinic acid Chemical compound COCCOC(=O)NCCCC[C@H](NC(=O)OCCOC)C(=O)NCCCCCCCOP(C)(O)=O WLCZTRVUXYALDD-IBGZPJMESA-N 0.000 claims description 4
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GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 4
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AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 claims description 4
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UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 4
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OCOKWVBYZHBHLU-UHFFFAOYSA-N Sobuzoxane Chemical compound C1C(=O)N(COC(=O)OCC(C)C)C(=O)CN1CCN1CC(=O)N(COC(=O)OCC(C)C)C(=O)C1 OCOKWVBYZHBHLU-UHFFFAOYSA-N 0.000 claims description 4
FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 4
108010066702 Thyrotropin Alfa Proteins 0.000 claims description 4
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GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 4
MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 4
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